This invention relates to novel structural analogues and derivatives of compounds with general analgesic or related pharmacological activity. In particular the invention relates to derivatives of opioid compounds, particularly morphine and related compounds.
A large range of therapeutic compounds is currently used in the treatment of conditions such as allergies, diarrhoea, migraine and other pain conditions, and in the treatment of congestive heart failure. These compounds include compounds with analgesic or related activities, such as anti-tussives, anti-depressants, local anaesthetics, anti-hypertensives, anti-asthmatics, anti-histamines, and anti-serotonins.
However, many of the therapeutic compounds of the types enumerated above have undesirable side-effects, such as the respiratory depression caused by opiates. In particular, many drugs which are useful for their action on the peripheral nervous system have undesirable effects in the central nervous system.
Thus opiates are the most powerful analgesics known, but their usefulness is greatly limited by their side-effects, including severe respiratory depression, and ability to induce addiction and physical dependence.
Despite intensive efforts to design analogues of morphine and related opioids which retain the analgesic activity but which do not have a deleterious effect on the central nervous system and the bowel, success has been limited. Structure-activity relationships have been extensively investigated, and a number of features have been widely accepted as essential. See for example xe2x80x9cAn Introduction to Pharmacologyxe2x80x9d by J. J. Lewis (E. and S. Livingston Ltd, 1964 Pages 401-407), and xe2x80x9cPrinciples of Drug Action: The Basis of Pharmacology (Ed. W. B. Pratt and P. Taylor; Churchill Livingstone, 3rd edition, 1990, Pages 25-27). In particular, it is generally considered that to retain analgesic activity the group on the tertiary nitrogen should be small, and should preferably be methyl; larger substituents are likely to be opiate receptor antagonists rather than agonists. Thus replacement of the methyl group of morphine by an allyl or cyclopropylmethyl moiety produces an antagonist. Although there are some exceptions to this rule, such as N-amylnormorphine and N-hexylnormorphine, in general a large substituent will result in antagonist activity.
We have attempted to modify the ability of biologically-active compounds to cross the blood-brain barrier by incorporating a highly polar group into the molecular structure. Thus we have shown that derivatives of the 2N atom of mianserin comprising a guanidino group show H1 and 5-hydroxytryptamine activity, but show no detectable activity in the central nervous system. In contrast, a compound in which the 2N atom of mianserin was substituted with a urea group still showed pronounced central nervous system activity (Jackson et al; Clin. Ex. Pharmacol. Physiol., 1992 19 17-23 and our U.S. Pat. No. 5,049,637).
Naltrexamine and oximorphamine have been modified by incorporation of groups which are zwitterionic at biological pH in order to restrict access to the central nervous system (Botros et al; J. Med. Chem., 1989 32 2068-2071, and Portoghese, U.S. Pat. No. 4,730,048). In U.S. Pat. No. 4,730,048 the zwitterionic group was added at C6. Some of these analogues were full agonists, and one was a strong antagonist.
A bis(t-butyldimethylsiloxy)-substituted compound in which a guanidino derivative was attached to the nitrogen via a 3 carbon spacer chain was found to show no opioid activity at xcexc-receptors in isolated guinea-pig ileum (Jackson et al, 1992). This suggested that such compounds would not have the desired activity.
Therefore there is a need for therapeutic compounds which have less activity within the central nervous system, thus having fewer undesirable side-effects, whilst at the same time having greater specificity of action on peripheral physiological mechanism. We have found that several compounds with the general formula outlined below not only have reduced central side-effects; but retain activity at desired peripheral receptors. In particular, those compounds which show activities at opioid receptors retain broad analgesic activity, contrary to current orthodoxy which teaches that the analgesic effects of opioids are mediated from the CNS. Their selectivity for peripheral opioid receptors not only makes them useful in for the treatment of pain without sedative or addictive effects, but also may make them useful for treatment of AIDS and related immune deficiency diseases.
In its broadest aspect, the invention provides an opioid compound of general formula I
[opioid-N]-[spacer]-[charged group],xe2x80x83xe2x80x83I
in which an opioid compound is linked via the nitrogen at position 17 to a spacer group, which in turn is linked to a charged group.
For the purposes of this specification, the term xe2x80x9copioid compoundxe2x80x9d is to be taken to mean a compound structurally related to morphine. The opioid compound preferably, but not necessarily, has opioid agonist or antagonist activity at opioid receptors.
The spacer can be any spacer group of dimensions approximately equivalent to an alkyl chain of 1 to 6 carbon atoms, and may for example be a straight or branched alkyl, alkenyl or alkynyl chain of 1 to 6 carbon atoms, which may optionally be susbstituted. The spacer also comprises a cyclic alkyl, alkenyl, or alkynyl group. Preferably the spacer group is unsubstituted, and more preferably is of 2 to 3 carbons atoms. The charged group may be any group which has the ability to restrict access of the compound of formula I to the central nervous system, and is preferably an amidine or guanidine group.
According to one embodiment, the present invention provides an opioid compound of general formula (II) 
in which
YNxe2x80x94 represents an organic residue obtained by removal of the R group from an opioid compound of general formula
YNxe2x80x94Rxe2x80x83xe2x80x83(IIIa)
xe2x80x83wherein R is H, alkyl of 1 to 6 carbon atoms, or cyclopropylmethyl,
xe2x80x83or of the general formula 
wherein R4 is methyl or ethyl, and
Y1xe2x80x94NR4 represents the corresponding organic residue;
Z is O, S or NR3;
R1 is H1, alkyl or aryloxyalkyl, wherein the aryl group is optionally substituted by alkyl, alkoxy, halogen, or alkyl substituted by halogen, and alkyl, alkoxy and the alkyl moiety of aryloxy alkyl have 1 to 6 carbon atoms;
R2 is H or an alkyl group having 1 to 6 carbon atoms;
R3 is H, alkyl, hydroxy, amino, cyano or acyl, wherein alkyl and acyl have 1 to 6 carbon atoms;
n is an integer of 1 to 6, and wherein
R1 and R3 may together complete an addition ring; then the grouping 
xe2x80x83may become a heterocyclic moiety such as 2-imidazolyl or 2-imidazolinyl: 
Preferably R is CH3.
Preferably n is 2 or 3.
Preferably Z is NH, and R1 and R2 are both H.
In order to indicate the trivalent N-atom more clearly, the structure of compounds of the formula (IIIa) may be written 
The precursors of YNxe2x80x94 and Y1NR4xe2x80x94 respectively are selected from compounds which are structurally related to morphine.
Thus the precursor of YNxe2x80x94 or Y1NR4xe2x80x94 is preferably a compound selected from the group consisting of morphine, codeine, heroin, ethylmorphine, O-carboxymethylmorphine, O-acetylmorphine, hydrocodone, hydromorphone, oxymorphone, oxycodone, dihydrocodeine, thebaine, metopon, etorphine, acetorphine, ketobemidone, ethohe ptazine, diprenorphine (M5050), buprenorphine, phenomorphan, levorphanol, pentazocine, eptazocine and metazocine.
Preferably the precursor is morphine, codeine or buprenorphine.
In a preferred embodiment, the compound of general formula I is one of the following: 
Typical examples of morphine-related compounds of the formula (IIIa) or (hIIc) are illustrated in Table 1. In each case the group R has been circled in order to clearly identify the residue YNxe2x80x94 or Y1N4xe2x80x94 as the remainder of the molecule.
The preferred precursors also include the unnamed compounds whose structures are shown in Table 1, with the nitrogen atom at position 17 indicated.
Thus the invention provides in a second broad aspect an opiate receptor agonist having analgesic properties and having reduced or no CNS activity. Preferably the opiate receptor agonist is a compound of general formula I or general formula II as defined above.
Where appropriate, the invention also includes pharmaceutically acceptable salts of the compounds of formula I, or formula II. A variety of pharmaceutically-acceptable salt-forming organic and inorganic acids is well known in the art.
According to a third aspect, the invention provides a method of reducing the central nervous system activity of an opioid compound, comprising the step of linking the nitrogen atom at position 17 of said compound to a spacer group, which in turn is linked to a charged group. Optionally the linkage to the charged group is via a spacer group.
According to a fourth aspect of the invention, methods for the preparation of the compounds of formula II are provided, as set out below, in which it will be appreciated that YNxe2x80x94 may be replaced by Y1NR4xe2x80x94:
1. By the reaction of a compound of formula
YNxe2x80x94Hxe2x80x83xe2x80x83(IV)
with a cyanamide, R 1NHCN, according to the equation 
2. By the reaction of a compound of formula (IV) with a compound of formula 
wherein L is a suitable leaving group, for example CH3O, CH3S, CH3SO2, SO3H, pyrazole or 
(3,5-dimethylpyrazol-1-yl)
according to the equation 
Compounds of the formula (II) wherein Z is S not only possess useful therapeutic activity per se, but may also be used as intermediates for the preparation of compounds of formula II wherein Z is NR2, eg.
3. By the reaction of a compound of the formula
YNxe2x80x94CNxe2x80x83xe2x80x83(VI)
with H2S there is obtained an N-thiocarboxamide YNxe2x80x94CS NH2, which may be reacted with an amine R1R2NH according to the two-stage equation 
to yield compounds of the invention where Z is S and where Z is NH.
4. The N-thiocarboxamide may also be methylated, for example using CH3I, to yield an isothiourea compound, which in turn may be reacted with an amine R1R2NH to yield a compound of the invention: 
5. An alternative method of synthesis of compounds of formula (II) comprises reacting an N-cyano compound of formula (VI) with methanol under acidic conditions to yield an isourea, which in turn is reacted with an amine according to the equation 
6. Compounds according to formula (II) where Z is N may also be prepared, for example from the N-cyano compound of formula (VI) and the appropriate metallated residue (for example, sodamide or metallated amines): 
7. Compounds of the formula (VI), most of which are also novel, and which are useful as intermediates in reactions 3, 5 and 6 above, are prepared by reacting a compound of formula (III) (see Table 1) with cyanogen bromide in a hydrocarbon solvent:
YNxe2x80x94R+BrCN♭YNxe2x80x94CN
8. Compounds of general formula (IV), which are useful as intermediates in reactions 1 and 2, are prepared from the compounds of formula (III) (Table 1) by the following reactions: 
Some compounds of the invention are optically active, and it will be clearly understood that both racemic mixtures and isolated stereoisomers are within the scope of the invention.
According to a fifth aspect, the invention provides a composition comprising as an effective agent a compound according to formula I, together with a pharmaceutically acceptable carrier.
Methods and pharmaceutical carriers for preparation of pharmaceutical compositions are well known in the art, as set out in textbooks such as Remington""s Pharmaceutical Sciences, 17th Edition, Mack Publishing Company, Easton, Pa., USA.
According to a sixth aspect, the invention provides a method of inducing analgesia, comprising the step of administering an effective amount of a compound of the invention to a mammal in need of such treatment. The mammal may be a human, or may be a domestic, companion or zoo mammal. Preferably the mammal is a human.
The dosage to be used will depend on the nature and severity of the condition to be treated, and will be at the discretion of the attending physician or veterinarian. The most suitable dosage for a specific condition can be determined using normal clinical trial procedures.
For the purposes of this specification it will be clearly understood that the word xe2x80x9ccomprisingxe2x80x9d means xe2x80x9cincluding but not limited toxe2x80x9d, and that the word xe2x80x9ccomprisesxe2x80x9d has a corresponding meaning.